Donor-specific antibodies (DSA) continue to be a substantial barrier to renal transplantation. DSA are directed at MHC antigens (alloantibody), tissue antigens, or ABO blood group carbohydrates. These antibodies are thought to arise from germinal center (GC) and marginal zone (MZ) B cells, respectively. Over 18,000 pa- tients on the kidney transplant waiting list have significant alloantibody levels, and 25% of living kidney donors is excluded due to ABO incompatibility. Anti-ABO antibodies cause rejection of kidney transplants by binding to donor vascular endothelium, leading to macrovascular thrombosis and organ loss. To avoid rejection in sen- sitized or ABO incompatible recipients, pre-transplant immune desensitization (IMDS) is needed. IMDS proto- cols combine several therapies: (i) removal of circulating DSA by therapeutic plasma exchange (PLEX) (ii) pooled intravenous immunoglobulin (IVIG) therapy to alter the fractional catabolism of DSA, (iii) pharmacologic plasma cell depletion to suppress DSA synthesis, and (iv) B-cell depleting therapies to decrease donor-specific memory B cells. However, many patients fail IMDS when DSA levels cannot be reduced to a threshold safe for a kidney transplant or when side effects occur, especially bleeding and infection. No widely-accepted tools currently exist to guide the timing, dosing, and selection of IMDS agents. [The overall objective of this project is to develop a mathematical model of immune desensitization as a clinical tool to guide personalized therapy. The specific goals are: (1) to construct and validate a differential equation model of anti-ABO IgG kinetics and clinical therapies for immune desensitization, including exploration of alternative models; (2) to test the hypothesis that PLEX and IVIG therapies alter anti-ABO IgG B cell homeostasis, and to extend the model so it accounts for this feature, if needed; (3) to validate the ability of the model developed in Aims 1 and 2 to predict the response of individual patients to IMDS therapy and potential complications. We will further develop a compartmental model of IgG synthesis and catabolism kinetics which accommodates actual clinical protocols. Anti-ABO antibody levels and B cell phenotypes will be measured in patients undergoing PLEX, IVIG and plasma cell depleting therapies. This data will be used to develop and refine the model, and to estimate model parameters. Finally, we will evaluate how well the model predicts the success or failure of immune desensitization in an independent sample of patients undergoing standard immune desensitization for ABO incompatible kidney transplantation, which combines PLEX, IVIG, and plasma- cell depleting therapies. ]

Public Health Relevance

This project proposes to develop a highly clinically applicable model to design treatment for a type of kidney transplantation. If successful, it would greatly advance the field of kidney transplantation, and improve the chances of success for a living donor, ABO incompatible kidney transplant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI098112-04
Application #
8762394
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Rice, Jeffrey S
Project Start
2011-12-01
Project End
2015-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Rosenberg, Alexander; Fucile, Christopher; White, Robert J et al. (2018) Visualizing nationwide variation in medicare Part D prescribing patterns. BMC Med Inform Decis Mak 18:103
Nogales, Aitor; Piepenbrink, Michael S; Wang, Jiong et al. (2018) A Highly Potent and Broadly Neutralizing H1 Influenza-Specific Human Monoclonal Antibody. Sci Rep 8:4374
Clark, Amelia M; DeDiego, Marta L; Anderson, Christopher S et al. (2017) Antigenicity of the 2015-2016 seasonal H1N1 human influenza virus HA and NA proteins. PLoS One 12:e0188267
Huang, Junqiong; Hilchey, Shannon P; Wang, Jiong et al. (2017) IL-15 enhances cross-reactive antibody recall responses to seasonal H3 influenza viruses in vitro. F1000Res 6:2015
Li, Dongmei; Xie, Zidian; Zand, Martin et al. (2017) Bon-EV: an improved multiple testing procedure for controlling false discovery rates. BMC Bioinformatics 18:1
Yang, Hongmei; Baker, Steven F; González, Mario E et al. (2016) An improved method for estimating antibody titers in microneutralization assay using green fluorescent protein. J Biopharm Stat 26:409-20
Sandal, Shaifali; Zand, Martin S (2015) Rational clinical trial design for antibody mediated renal allograft injury. Front Biosci (Landmark Ed) 20:743-62
Wang, Jiong; Hilchey, Shannon P; Hyrien, Ollivier et al. (2015) Multi-Dimensional Measurement of Antibody-Mediated Heterosubtypic Immunity to Influenza. PLoS One 10:e0129858
Qiu, Xing; Wu, Shuang; Hilchey, Shannon P et al. (2015) Diversity in Compartmental Dynamics of Gene Regulatory Networks: The Immune Response in Primary Influenza A Infection in Mice. PLoS One 10:e0138110
Wu, Hulin; Miao, Hongyu; Xue, Hongqi et al. (2015) Quantifying Immune Response to Influenza Virus Infection via Multivariate Nonlinear ODE Models with Partially Observed State Variables and Time-Varying Parameters. Stat Biosci 7:147-166

Showing the most recent 10 out of 15 publications